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    Summary
    EudraCT Number:2019-000138-20
    Sponsor's Protocol Code Number:AL001-2
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-15
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-000138-20
    A.3Full title of the trial
    A Phase 2, Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AL001 in Heterozygous Carriers of Granulin or C9ORF72 Mutations Causative of Frontotemporal Dementia
    Studio di fase 2, multicentrico, in aperto per valutare sicurezza, tollerabilità, farmacocinetica e farmacodinamica di AL001 in portatori eterozigoti di mutazioni dei geni Granulina o C9orf72 responsabili di demenza frontotemporale
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open-Label Study to Evaluate Safety of long-term AL001 dosing in FTD
    Studio in aperto per valutare la sicurezza della somministrazione a lungo termine di AL001 nella FTD
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    A.4.1Sponsor's protocol code numberAL001-2
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAlector Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAlector Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlector Inc.
    B.5.2Functional name of contact pointKristina Vlaovic
    B.5.3 Address:
    B.5.3.1Street Address131 Oyster Point Boulevard, Suite 600
    B.5.3.2Town/ citySouth San Francisco
    B.5.3.3Post codeCA 94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number+16508269572
    B.5.6E-mailkristina.vloavic@alector.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAL001
    D.3.2Product code [AL001]
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeAL001
    D.3.9.4EV Substance CodeSUB193428
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Frontotemporal Dementia
    Demenza frontotemporale
    E.1.1.1Medical condition in easily understood language
    A type of dementia that causes problems with behaviour and language
    Un tipo di demenza che provoca problemi di comportamento e linguaggio
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10068968
    E.1.2Term Frontotemporal dementia
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety and tolerability of intravenous (IV) administration of AL001 over 48 weeks in asymptomatic and symptomatic carriers of a granulin (GRN) mutation causative of frontotemporal dementia (FTD) and in symptomatic carriers of a C9orf72 mutation causative of FTD.
    Valutare la sicurezza e la tollerabilità della somministrazione endovenosa (EV) di AL001 fino a 48 settimane in portatori asintomatici e sintomatici di una mutazione del gene granulina (GRN) responsabile di demenza frontotemporale (FTD) e in portatori sintomatici di una mutazione di C9orf72 responsabile di FTD.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to evaluate the effect of IV administration of AL001 over 48 weeks in asymptomatic and symptomatic carriers of a GRN mutation causative of FTD and in symptomatic carriers of a C9orf72 mutation causative of FTD on the following:
    •Pharmacokinetics (PK)
    •Longitudinal plasma and cerebrospinal fluid (CSF) progranulin (PGRN) concentration levels.
    •Longitudinal levels of sortillin 1 (SORT1) on white blood cells (WBCs) and soluble sortillin-1 (sSORT1) levels in CSF
    Gli obiettivi secondari di questo studio sono la valutazione dell'effetto della somministrazione EV di AL001 fino a 48 settimane in portatori asintomatici e sintomatici di una mutazione di GRN responsabile di FTD e in portatori sintomatici di una mutazione di C9orf72 responsabile di FTD rispetto a:
    • Farmacocinetica (PK)
    • Livelli longitudinali della concentrazione di progranulina (PGRN) nel plasma e nel liquido cerebrospinale (CSF).
    • Livelli longitudinali della sortilina 1 (SORT1) sui globuli bianchi (WBC) e livelli di sortilina 1 solubile (sSORT1) nel CSF
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Participants must meet all of the key inclusion criteria specific to their applicable participant category. These bullet points are some of the important criteria within each category:

    1) Participant completed Study AL001-1 through the Day 57 visit and did not experience AEs that the investigator deems would prevent safe participation in Study AL001-2.
    2) Participant meets 1 or more of the 6 behavioral/cognitive symptoms required for a diagnosis of possible behavioral variant frontotemporal dementia (bvFTD; Rascovsky 2011) or has diagnosis of primary progressive aphasia (PPA; Gorno Tempini 2011)
    3) Participant completed Study AL001-1 through the Day 43 visit and did not experience AEs that the investigator deems would prevent safe participation in Study AL001-2.
    4) Participant is a carrier of a loss of function GRN mutation causative of FTD and known their mutation status
    5) Participant has a CDR® plus NACC global score of 0.5, 1, or 2; and 1 or more of the 6 behavioral/cognitive symptoms required for a diagnosis of possible bvFTD (Rascovsky 2011) or a diagnosis of PPA (Gorno Tempini 2011)

    In addition, this is the list of the important inclusion criteria:

    • Participants are 18 to 85 years of age.
    • At screening, female participants must be nonpregnant and nonlactating, and at least one of the following conditions must apply:
    - Participant is not a woman of childbearing potential (WOCBP) (either surgically sterilized or physiologically incapable of becoming pregnant, or at least 1 year postmenopausal [amenorrhea duration of 12 consecutive months with no identified cause other than menopause]).
    - Participant is a WOCBP and using an acceptable contraceptive method from screening until 8 weeks after the last dose of study drug. Acceptable contraception is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. In addition, total abstinence, in accordance with the lifestyle of the participant, is acceptable.
    - A WOCBP must have a serum pregnancy test conducted at screening. Additional requirements for pregnancy testing during and after study intervention are located in the Schedule of Assessments (Table 14-1 in the protocol).
    • Male participants, if not surgically sterilized, must agree to use acceptable contraception and not donate sperm from Day 1 until 8 weeks after the last dose of study drug.Acceptable contraception for the male patient (and his female partner) is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. In addition, total abstinence, in accordance with the lifestyle of the participant, is acceptable.
    • Participant is in good physical health on the basis of no clinically significant findings from medical history, PEs, laboratory tests, ECGs, and vital signs.
    • Participant agrees not to donate blood or blood products for transfusion for the duration of the study and for 1 year after final dose of study drug.
    • Participant is willing and has the ability to comply with the study protocol requirements, in the opinion of the investigator.
    • Participant is willing and able to give informed consent. If the study participant is not competent, a legally authorized representative must provide informed consent on their behalf, and the participant must provide assent, in accordance with the local regulations, guidelines, and institutional review board (IRB) or independent ethics committee (IEC).
    Please refer to the protocol for the full list.
    Il partecipante soddisfa tutti i criteri specifici della categoria applicabile al partecipante. Questi punti dell’elenco sono alcuni dei criteri importanti all'interno di ciascuna categoria:
    1) Il paziente ha completato lo Studio AL001 1 fino alla visita del Giorno 57 e non ha manifestato eventi avversi (AE) che lo sperimentatore ritenga possano impedire la partecipazione sicura allo Studio AL001 2.
    2) Il paziente partecipante soddisfa 1 o più dei 6 sintomi comportamentali/cognitivi necessari per la diagnosi di i criteri diagnostici per possibile variante comportamentale della demenza frontotemporale (bvFTD; Rascovsky 2011) o presenta una diagnosi di probabile bvFTD (Rascovsky 2011) o afasia progressiva primaria (PPA; ) (Gorno Tempini 2011).
    3) Il partecipante ha completato lo Studio AL001 1 fino alla visita del Giorno 43 e non ha manifestato eventi avversi che lo sperimentatore ritiene possano impedire la partecipazione sicura allo Studio AL001 2.
    4) Il paziente è portatore di una mutazione con perdita di funzionalità di GRN responsabile di FTD ed è a conoscenza del proprio stato mutazionale
    5) Il paziente partecipante presenta un punteggio globale nei Domini di Comportamento e Linguaggio della degenerazione lobare frontotemporale secondo la Valutazione clinica della demenza mediante lo Strumento di stadiazione della demenza PLUS del Centro di coordinamento nazionale per la malattia di Alzheimer (Clinical Dementia Rating Dementia Staging Instrument PLUS National Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains, [CDR® plus NACC FTLD]) pari a 0,5, 1 o 2; e manifesta 1 o più dei 6 sintomi comportamentali/cognitivi necessari per la diagnosi di possibile bvFTD (Rascovsky 2011) o una diagnosi di PPA (Gorno-Tempini 2011).

    Inoltre, questo è l'elenco dei criteri di inclusione importanti:
    • I partecipanti hanno età compresa tra 18 e 85 anni.
    • Allo screening, le partecipanti di sesso femminile non devono essere in stato di gravidanza e in allattamento, e deve applicarsi almeno una delle seguenti condizioni:
    - La partecipante non è una donna in età fertile (WOCBP) (chirurgicamente sterile oppure fisiologicamente non in grado di entrare in gravidanza, o in post-menopausa da almeno 1 anno [durata dell'amenorrea di 12 mesi consecutivi senza causa identificata diversa dalla menopausa]).
    - La partecipante è una WOCBP che utilizza un metodo di contraccezione accettabile dallo screening fino a 8 settimane dopo l'ultima dose di farmaco in studio. Si definisce metodo di contraccezione accettabile l'utilizzo di contraccettivi ormonali o
    un dispositivo intrauterino in combinazione con almeno 1 dei seguenti metodi di contraccezione: diaframma, cappuccio cervicale o preservativo. Inoltre, l'astinenza totale, secondo lo stile di vita della partecipante, è
    accettabile.
    - Una WOCBP deve essere sottoposta a un test di gravidanza sul siero effettuato allo screening. Ulteriori requisiti per i test di gravidanza durante e dopo l'intervento dello studio sono disponibili nel Programma delle valutazioni (Tabella 14-1 del protocollo).
    • I partecipanti di sesso maschile, se non sterilizzati chirurgicamente, devono accettare di utilizzare un metodo di contraccezione accettabile e di non donare sperma dal Giorno 1 fino a 8 settimane dopo l'ultima dose di farmaco in studio. Si definisce metodo di contraccezione accettabile per il paziente di sesso maschile (e la sua partner) l’utilizzo di contraccettivi ormonali o di un dispositivo intrauterino in combinazione con almeno 1 dei seguenti metodi di contraccezione: diaframma, cappuccio cervicale o preservativo. Inoltre, è accettabile l'astinenza totale, secondo lo stile di vita della partecipante.
    Fare riferimento al protocollo per la lista completa.
    E.4Principal exclusion criteria
    • Participant has a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins.
    • Participant has history of substance use disorder (drug or alcohol) within the past 2 years, with the exception of nicotine, as defined by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria (American Psychiatric Association 2013).
    • Participant has donated or lost more than 100 mL of blood within 30 days prior to Day 1.
    • Participant has had a blood transfusion within 30 days prior to screening.
    • Participant has had clinically significant and/or acute illness within 5 days prior to drug administration that may affect safety assessments.
    • Participant had surgery, hospitalization, or clinically significant infection requiring oral or IV antibiotics during the 30 days prior to screening.
    • Participant has planned procedure or surgery during the study that would interfere with the ability to perform study assessments.
    • Participant has past history of seizures, with the exception of childhood febrile seizures.
    • Participant has clinically, significant systemic immunocompromised condition because of continuing effects of immune suppressing medication.
    • Participant has major depressive disorder or history of schizophrenia, schizoaffective disorder, or bipolar disorder.
    • Participant has history of cancer
    • Participant has history or presence of intracranial tumor that is clinically relevant.
    • Participant has any clinically significant medical condition or laboratory abnormality that precludes the participant’s safe participation in and completion of the study.
    • Participant is positive for hepatitis B surface antigen, hepatitis C virus antibodies, or human immunodeficiency virus 1 and 2 antibodies or antigen, or history of spirochetal infection of the CNS.
    • Participant has significant kidney disease as indicated by a screening creatinine clearance <30 mL/min as calculated by the central laboratory using the Cockcroft Gault formula, which remains <30 mL/min if retested.
    • Participant has impaired hepatic function as indicated by screening aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >=2.5 the upper limit of normal (ULN) or total bilirubin >=2.0 × ULN, which remains above either of these limits if retested or other abnormalities in synthetic function that are clinically significant.
    • The participant has, within the last 2 years, had unstable or clinically significant cardiovascular disease.
    • Participant has uncontrolled hypertension.
    • Participant has history or presence of an abnormal ECG that is clinically significant including complete left bundle branch block, second or third degree heart atrioventricular block, or evidence of prior acute or subacute myocardial infarction or ischemia.
    • Participant has QT interval corrected using Fridericia formula (QTcF) >450 ms for male participants and >470 ms for female participants.
    • Participant has history of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease, coronary heart disease, clinically significant electrolyte abnormalities, or family history of sudden unexplained death or long QT syndrome.
    • Participant has contraindication to lumbar dural puncture.
    • Participant has dementia or a milder, symptomatic syndrome (eg, mild cognitive impairment, mild behavioral impairment, or mild motor impairment) due to a condition other than FTD, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, Huntington disease, or vascular dementia.
    • Participant has history or presence of clinically evident vascular disease potentially affecting the brain that has the potential to affect cognitive function.
    Please refer to the protocol for the full list.
    •Il partecipante ha un’anamnesi nota di reazione allergica grave, reazione anafilattica o altra reazione di ipersensibilità agli anticorpi chimerici, umani o umanizzati o alle proteine di fusione.
    • Il partecipante presenta un’anamnesi di disturbo da abuso di sostanze (alcol o di altre sostanze), a accezione della nicotina (secondo il DSM-5) negli ultimi 2 anni.
    • Il partecipante ha donato o perso più di 100 ml di sangue entro 30 giorni prima del Giorno 1.
    • Il partecipante è stato sottoposto a trasfusione sanguigna entro 30 giorni prima dello screening.
    • Il partecipante ha avuto, entro 5 giorni prima della somministrazione del farmaco, una malattia clinicamente significativa e/o acuta che potrebbe influire sulle valutazioni di sicurezza.
    • Il partecipante ha subito un intervento chirurgico, un ricovero ospedaliero o ha avuto un'infezione clinicamente significativa che abbia richiesto antibiotici per via orale o EV durante i 30 giorni precedenti allo screening.
    • Il partecipante deve essere sottoposto a una procedura o un intervento chirurgico programmato durante lo studio in grado di interferire con la capacità di effettuare le valutazioni dello studio.
    • Il partecipante ha un’anamnesi pregressa di convulsioni, ad eccezione di crisi febbrili nell’infanzia.
    • Il partecipante ha una condizione immunocompromessa sistemica clinicamente significativa, a causa dei continui effetti del farmaco immunosoppressivo.
    • Il partecipante presenta un disturbo depressivo maggiore o un’anamnesi di schizofrenia, disturbo schizoaffettivo o disturbo bipolare.
    • Il partecipante ha un’anamnesi di tumore
    • Il partecipante ha un’anamnesi o presenta un tumore intracranico clinicamente rilevante.
    • Il partecipante presenta una qualsiasi condizione medica clinicamente significativa o anomalia di laboratorio che gli precluda la partecipazione sicura e il completamento dello studio.
    • Il partecipante è positivo all'antigene di superficie dell'epatite B, agli anticorpi per il virus dell'epatite C o agli anticorpi o all'antigene per il virus dell'immunodeficienza umana 1 e 2 oppure ha un’anamnesi di infezione da spirochete del SNC.
    • Il partecipante ha una malattia renale significativa cronica indicata da una clearance della creatinina allo screening di <30 ml/min, secondo il calcolo effettuato dal laboratorio centrale mediante la formula di Cockcroft-Gault, che rimane di <30 ml/min se testata nuovamente.
    • Il partecipante presenta funzionalità epatica compromessa come indicato dallo screening dell'aspartato aminotransferasi (AST) o dell'alanina aminotransferasi (ALT) >=2.5 rispetto al limite superiore della norma (ULN) o della bilirubina totale >=2.0 × ULN, che permane al di sopra di tali limiti se testato nuovamente o altre anomalie della funzionalità sintetica clinicamente significative.
    • Il partecipante ha avuto, negli ultimi 2 anni, una malattia cardiovascolare instabile o clinicamente significativa.
    • Il partecipante presenta ipertensione non controllata.
    • Il partecipante ha un’anamnesi o presenta un ECG anomalo clinicamente significativo.
    Fare riferimento al protocollo per l'elenco completo.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Safety Endpoints:
    To assess the potential effect of cumulative exposure on the safety profile of AL001, the following will be evaluated by dose, such as by using tertiles of the actual
    dose (normalized to weight) received:
    • Incidence, nature, and severity of AEs and SAEs
    • Incidence of treatment discontinuations and study discontinuations due to AEs
    • Physical examination abnormalities
    • Neurological examination abnormalities
    • Changes in vital signs from baseline over time
    • Changes in ECGs from baseline over time
    • MRI abnormalities after dosing relative to baseline
    • Changes in clinical laboratory tests from baseline over time
    • Sheehan Suicidality Tracking Scale (Sheehan-STS)
    • Incidence of ADAs to AL001
    Per valutare il potenziale effetto dell'esposizione cumulativa sul profilo di sicurezza di AL001, verrà valutato quanto segue in base alla dose, ad esempio utilizzando terzili della dose attuale (normalizzata rispetto al peso) ricevuta:
    • Incidenza, natura e gravità degli AE e SAE
    • Incidenza di sospensione del trattamento e dello studio a causa di AE
    • Anomalie riscontrate nell'esame obiettivo
    • Anomalie riscontrate nell'esame neurologico
    • Variazioni delle funzioni vitali rispetto alla baseline nel tempo
    • Variazioni degli ECG rispetto alla baseline nel tempo
    • Anomalie dei risultati RMI dopo la somministrazione rispetto alla baseline
    • Variazioni dei test clinici di laboratorio rispetto alla baseline nel tempo
    • Sheehan Suicidality Tracking Scale (Sheehan-STS)
    • Incidenza degli ADA rispetto a AL001
    E.5.1.1Timepoint(s) of evaluation of this end point
    AEs: will be summarized if applicable
    Laboratory data: at base line and at scheduled timepoints
    Vital signs: at base line and at scheduled timepoints
    ECG: at baseline and at scheduled timepoints
    Physical examinations: at Screening and at scheduled timepoints or as clinically indicated
    Neurological examinations and Sheehan-STS: At Screening and at scheduled timepoints
    ADA: at baseline and at scheduled timepoints
    AE: saranno sintetizzati se applicabile
    Dati di laboratorio: alla baseline e in momenti temporali programmati
    Funzioni vitali: alla baseline e in momenti temporali programmati
    ECG: alla baseline e in momenti temporali programmati
    Esami obiettivi: allo screening e in momenti temporali programmati o come clinicamente indicato
    Esami neurologici e Sheehan-STS: Allo Screening e in momenti temporali programmati
    ADA: alla baseline e in momenti temporali programmati
    E.5.2Secondary end point(s)
    Secondary Pharmacokinetic (PK) Endpoints:
    • Serum concentration of AL001 at specified time
    points
    • AL001 PK parameters (if data permit)
    - Cmax
    - Ctrough
    - AUCss
    Secondary Pharmacodynamic (PD) Biomarker Endpoints:
    • The overall change from baseline in PGRN in CSF
    • The overall change from baseline in PGRN in plasma
    The overall change from baseline in SORT1 on WBCs and sSORT1 in CSF

    The exploratory objectives of this study are to assess the effect of IV administration of AL001 over up to 48 weeks in asymptomatic and symptomatic carriers of a GRN mutation causative of FTD and in symptomatic carriers of a C9orf72 mutation causative of FTD on the following:

    Exploratory PD Biomarker Objectives:

    • Longitudinal blood, plasma, and CSF concentration levels of exploratory biomarkers of neurodegeneration, lysosomal function, and microglial activity
    • MRI measures to evaluate changes in the brain
    • Brain microglial activation (for participants who agree to participate in this optional assessment only; see protocol Appendix 3 [Section 14.3] and Appendix 4 [Section 14.4])
    • Correlations among exploratory fluid PD biomarkers, imaging PD measures, and COAs
    • Clinical progression as measured by COAs
    Endpoint secondari di farmacocinetica (PK):
    • Concentrazione nel siero di AL001 in momenti temporali specifici
    • Parametri di PK di AL001 (se i dati lo consentono)
    - Cmax
    - Cmin
    - AUCss
    Endpoint secondari dei biomarcatori di farmacodinamica (PD):
    • Variazione complessiva rispetto alla baseline di PGRN nel CSF
    • Variazione complessiva rispetto alla baseline di PGRN nel plasma
    Variazione complessiva rispetto alla baseline di SORT1 su WBC e sSORT1 nel CSF.
    Gli obiettivi esplorativi di questo studio sono la valutazione dell'effetto della somministrazione EV di AL001 fino a 48 settimane in portatori asintomatici e sintomatici di una mutazione di GRN responsabile di FTD e in portatori sintomatici di una mutazione di C9orf72 responsabile di FTD rispetto a:
    Obiettivi esplorativi dei biomarcatori di PD:
    • Livelli longitudinali della concentrazione nel sangue, nel plasma e nel CSF di biomarcatori esplorativi di neurodegenerazione, funzione lisosomiale e attività microgliale
    • Misurazioni di RMI per valutare le variazioni cerebrali
    • Attivazione microgliale cerebrale (soltanto per i partecipanti che accettano di partecipare a tale valutazione facoltativa; vedere l’Appendice 3 [Sezione 14.3] e l’Appendice 4 [Sezione 14.4] del protocollo)
    • Correlazioni tra biomarcatori esplorativi di PD nei liquidi, misurazioni di imaging di PD e valutazioni degli esiti clinici (COA)
    • Progressione clinica misurata mediante COA
    E.5.2.1Timepoint(s) of evaluation of this end point
    For Pharmacokinetic (PK), at day 1, day 10, day 29, day 57, day 85, day 113, day 141, day 169, day 197, day 225, day 253, day 281, day 309, day 337 and at study completion.

    For Pharmacodynamic (PD), at day 1, day 10, day 29, day 57, day 85, day 113, day 141, day 169, day 197, day 225, day 253, day 281, day 309, day 337 and at study completion.
    Per farmacocinetica (PK), al giorno 1, giorno 10, giorno 29, giorno 57, giorno 85, giorno 113, giorno 141, giorno 169, giorno 197, giorno 225, giorno 253, giorno 281, giorno 309, giorno 337 e al completamento dello studio.
    Per farmacodinamica (PD), al giorno 1, giorno 10, giorno 29, giorno 57, giorno 85, giorno 113, giorno 141, giorno 169, giorno 197, giorno 225, giorno 253, giorno 281, giorno 309, giorno 337 e al completamento dello studio.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    In aperto
    Open
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    United States
    Germany
    Italy
    Netherlands
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days8
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days8
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 17
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    If the study participant is not competent, a legally authorised representative must provide informed consent on their behalf, and the participant must provide assent, in accordance with the local regulations, guidelines, and ethics committees.
    Se il partecipante dello studio non è in grado, un rappresentante legalmente autorizzato deve fornire il consenso informato per suo conto e il partecipante deve fornire l’assenso, in conformità a normative locali, linee guida e comitati etici locali.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 17
    F.4.2.2In the whole clinical trial 32
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    According to their standard of care
    Secondo il loro standard di cura
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-09-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-30
    P. End of Trial
    P.End of Trial StatusOngoing
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